The Inside Out of Neurocutaneous · PDF file · 2010-09-15Dental anomalies and...

The Inside Out of The Inside Out of Neurocutaneous DisordersNeurocutaneous Disorders

Robert GreenwoodRobert Greenwood

Sometimes spots and knots have a purpose that tells you something about the organism that has them.

OxymoronsOxymorons That Will Not Be That Will Not Be Used In This LectureUsed In This Lecture

Black Light Black Light Never generalize!!Never generalize!!Exact estimateExact estimate

Neurocutaneous DisordersNeurocutaneous DisordersGeneral ConceptsGeneral Concepts1.1. The skin can be a window that allows you to see the The skin can be a window that allows you to see the

medical future of an infant.medical future of an infant.2.2. The cutaneous signs can be subtle.The cutaneous signs can be subtle.3.3. As in many other genetic diseases variable penetrance and As in many other genetic diseases variable penetrance and

expression are the rule. expression are the rule. 4.4. Family history and examination of other family members is Family history and examination of other family members is

a very important tool in making a diagnosis. a very important tool in making a diagnosis. 5.5. Hair and teeth are skin appendages and are often affected Hair and teeth are skin appendages and are often affected

when skin is affected. when skin is affected. 6.6. Look on the WebLook on the Web

http://tray.dermatology.uiowa.edu/DDX/macule.htmlhttp://tray.dermatology.uiowa.edu/DDX/macule.htmlhttp://http://dermatlas.med.jhmi.edu/dermdermatlas.med.jhmi.edu/derm//http://http://dermatology.cdlib.orgdermatology.cdlib.org//http://dermis.net/doia/mainmenu.asp?zugr=d&lang=ehttp://dermis.net/doia/mainmenu.asp?zugr=d&lang=e

Neurocutaneous DisordersNeurocutaneous Disorders

1.1. Neurofibromatosis I & IINeurofibromatosis I & II2.2. Tuberous SclerosisTuberous Sclerosis3.3. Von Von HippelHippel LindauLindau diseasedisease4.4. SturgeSturge Weber SyndromeWeber Syndrome5.5. KlippelKlippel--TrenaunayTrenaunay--WeberWeber SyndromeSyndrome6.6. OslerOsler--WeberWeber--RenduRendu SyndromeSyndrome7.7. WyburnWyburn--Mason SyndromeMason Syndrome8.8. Linear Linear SebaciousSebacious Nevus SyndromeNevus Syndrome9.9. Neurocutaneous Neurocutaneous MelanosisMelanosis10.10. WaardenburgWaardenburg Syndrome Type 1 & 2Syndrome Type 1 & 211.11. Fabry'sFabry's DiseaseDisease

Neurocutaneous DisordersNeurocutaneous DisordersIncidenceIncidence

Neurofibromatosis Neurofibromatosis type 1type 1Tuberous SclerosisTuberous SclerosisAtaxia Ataxia TelangiectasiaTelangiectasiaXerodermaXerodermaPigmentosumPigmentosumNeurofibromatosis Neurofibromatosis type 2type 2

1/1,0001/1,000--1/7,8001/7,800(30/100,000)(30/100,000)10.6/100,00010.6/100,0001.7/100,0001.7/100,0001/100,000 1/100,000 -- 1/250,0001/250,000

1/200,0001/200,000

Neurocutaneous DisordersNeurocutaneous DisordersIndentifiedIndentified Chromosome DefectsChromosome DefectsDisorderDisorder

NF1NF1NF2NF2TSTSIncontinentiaIncontinentia PigmentiPigmentiHypomelanosisHypomelanosis of Itoof Ito

AA--TTVon Von HippleHipple LindauLindau

OslerOsler –– RenduRendu --Weber Weber DiseaseDisease

ChromosomeChromosome

17q11.217q11.222q12.222q12.216p13.3, 12q14, 9q3416p13.3, 12q14, 9q34Xq28Xq28 -- XX--linked dominantlinked dominant? 9q33? 9q33--qter, 15q11qter, 15q11--q13, q13, and Xp11and Xp1111q22.311q22.311q13, 3p2611q13, 3p26--p25p25

9q34.19q34.1

Neurocutaneous DisordersNeurocutaneous DisordersInheritanceInheritance

Autosomal DominantAutosomal DominantAutosomal RecessiveAutosomal RecessiveXX--linked Recessivelinked RecessiveSporadicSporadic

Genetics Principles: NF1 and Genetics Principles: NF1 and Other Neurocutaneous DisordersOther Neurocutaneous Disorders

PenetrancePenetranceExpressionExpression–– Variable expressivityVariable expressivity

PleiotropyPleiotropyMosaicismMosaicismHeterogeneityHeterogeneity-- locus and alleliclocus and allelic

Neurocutaneous DiseasesNeurocutaneous DiseasesAutosomal Dominant InheritanceAutosomal Dominant Inheritance

Neurofibromatosis Neurofibromatosis Tuberous SclerosisTuberous SclerosisVon Von HippelHippel--LindauLindau DiseaseDiseaseLentiginosisLentiginosis--DeafnessDeafness--CardiopathyCardiopathy SyndSynd..HypomelanosisHypomelanosis of Itoof ItoOslerOsler--WeberWeber--RenduRendu DiseaseDisease

Neurocutaneous DiseasesNeurocutaneous DiseasesAutosomal Recessive InheritanceAutosomal Recessive Inheritance

AtaxiaAtaxia--TelangiectasiaTelangiectasiaXerodermaXeroderma PigmentosumPigmentosumCockayneCockayne’’ss SyndromeSyndromeRothmundRothmund--Thomson SyndromeThomson SyndromeSjogrenSjogren--Larsson SyndromeLarsson SyndromeNeuroichthyosisNeuroichthyosisWerner Syndrome and Werner Syndrome and ProgeriaProgeria

Neurocutaneous DiseasesNeurocutaneous DiseasesXX--Linked InheritanceLinked Inheritance

IncontinentiaIncontinentia PigmentiPigmenti

Neurocutaneous DiseasesNeurocutaneous DiseasesSporadic Congenital and Sporadic Congenital and AngiomatosesAngiomatoses

Neurocutaneous Neurocutaneous MelanosisMelanosisLinear Sebaceous NevusLinear Sebaceous NevusSturgeSturge--Weber SyndromeWeber SyndromeKlippelKlippel--TrenaunayTrenaunay SyndromeSyndromeWyburnWyburn--Mason SyndromeMason Syndrome

Classification of Classification of Neurocutaneous Disorders and Neurocutaneous Disorders and CancerCancer

OncogeneOncogene or tumor suppressor gene or tumor suppressor gene abnormalities. abnormalities.

–– Caretaker Caretaker -- does not control cell growth directly does not control cell growth directly but instead controls the rate of mutation but instead controls the rate of mutation

–– GatekeeperGatekeeper-- controls either the rate of cell birth controls either the rate of cell birth or the rate of cell deathor the rate of cell death

Familial Cancer SyndromesFamilial Cancer Syndromes--Disorders of the CaretakersDisorders of the Caretakers

Nucleotide Excision Repair Syndromes: Nucleotide Excision Repair Syndromes: XerodermaXerodermaPigmentosumPigmentosum, , CockayneCockayne Syndrome, and Syndrome, and TrichothiodystrophyTrichothiodystrophyAtaxiaAtaxia--TelangiectasiaTelangiectasiaBloom SyndromeBloom SyndromeFanconiFanconi AnemiaAnemiaHereditary Hereditary NonpolyposisNonpolyposis Colorectal Cancer (HNPCC)Colorectal Cancer (HNPCC)Werner SyndromeWerner SyndromePeutzPeutz--JeghersJeghers SyndromeSyndromeJuvenile Juvenile PolyposisPolyposis SyndromeSyndrome

Nucleotide Excision Repair Nucleotide Excision Repair (NER) Defects(NER) Defects

XerodermaXeroderma pigmentosumpigmentosum (XP)(XP)CockayneCockayne syndrome (CS)syndrome (CS)Photosensitive form of Photosensitive form of trichothiodystrophytrichothiodystrophy(TTD)(TTD)

Nucleotide Excision Repair Nucleotide Excision Repair (NER) Defects(NER) Defects

All are recessiveAll are recessiveAll have extreme sunlight sensitivity and 1000X frequency All have extreme sunlight sensitivity and 1000X frequency skin cancersskin cancersProgressive degeneration of skin and eyesProgressive degeneration of skin and eyesIn some accelerated neurologic degeneration and neuronal In some accelerated neurologic degeneration and neuronal deathdeathKey features CS and TTDKey features CS and TTD–– CSCS-- short stature, severe neurological abnormalities with short stature, severe neurological abnormalities with

dysmyelination, cataracts, birddysmyelination, cataracts, bird--like facelike face–– TTDTTD-- brittle hair and nails, ichthiosis, other symptoms similar to brittle hair and nails, ichthiosis, other symptoms similar to

CSCS

XerodermaXeroderma PigmentosaPigmentosa

Skin abnormalitiesSkin abnormalities–– Erythema and Erythema and bullaebullae (acute sensitivity in infancy)(acute sensitivity in infancy)–– FrecklesFreckles–– XerosisXerosis (dryness) and scaling(dryness) and scaling–– Areas of Areas of hyperpigmentationhyperpigmentation alternating with alternating with hyporpigmentationhyporpigmentation–– TelangiectasiaTelangiectasia–– AtrophyAtrophy–– Benign lesion: actinic Benign lesion: actinic keratoseskeratoses, , keratocanthomaskeratocanthomas, , angiomasangiomas, ,

fibromasfibromas–– Malignant lesions: basal cell carcinoma, Malignant lesions: basal cell carcinoma, squamoussquamous cell cell

carcinoma, melanomacarcinoma, melanomaOphthalmologic abnormalities Ophthalmologic abnormalities ConjunctivitusConjunctivitus with with photophobia, photophobia, lacrimationlacrimation, edema, edema–– Cornea: Cornea: keratitiskeratitis, , opacificationopacification, impaired vision, impaired vision–– Neoplasms of conjunctiva, cornea, and lidsNeoplasms of conjunctiva, cornea, and lids

XX--PP

XerodermaXeroderma PigmentosaPigmentosaNeurologic ManifestationsNeurologic Manifestations

MicrocephalyMicrocephalyLow intelligenceLow intelligenceProgressive mental deteriorationProgressive mental deteriorationProgressive Progressive sensorineuralsensorineural deafnessdeafnessAbnormal motor activityAbnormal motor activityHyporeflexiaHyporeflexia or or areflexiaareflexiaPrimary neuronal degenerationPrimary neuronal degeneration

AtaxiaAtaxia--TelangiectasiaTelangiectasia (A(A--T)T)

1.1. Progressive gait and Progressive gait and truncaltruncal ataxia with ataxia with onset from 1 to 3 years of age; onset from 1 to 3 years of age; progressively slurred speech; progressively slurred speech;

2.2. ChoreoathetosisChoreoathetosis, seizures, , seizures, 3.3. OculomotorOculomotor apraxia, apraxia, 4.4. OculocutaneousOculocutaneous telangiectasiatelangiectasia, usually by 6 , usually by 6

years of age;years of age;

Ataxia Ataxia TelangiectasiaTelangiectasiaTelangiectaticTelangiectatic lesions of lesions of conjuctivaeconjuctivae, , malarmalar eminences, ear lobes and upper eminences, ear lobes and upper neckneckAtaxia, Ataxia, choreoathetosischoreoathetosis and and nystagmusnystagmusImmunologic deficienciesImmunologic deficienciesCancer pronenessCancer proneness-- 38% 38% lymphoreticularlymphoreticular

Ataxia Ataxia TelangiectasiaTelangiectasia

AA--TT

IncidenceIncidence-- 1/40,000 births1/40,000 birthsCarrier frequency 1 %Carrier frequency 1 %Female carriers RR of 5 for breast cancerFemale carriers RR of 5 for breast cancerChromosome 11q22.3Chromosome 11q22.3-- ATMATM (ataxia(ataxia--telangiectasiatelangiectasiamutated), is a member of a family of phosphatidylinositolmutated), is a member of a family of phosphatidylinositol--33--kinasekinase––related genes involved in cell cycle control, related genes involved in cell cycle control,

intracellular protein transport, and DNA damage responseintracellular protein transport, and DNA damage response

IncontinentiaIncontinentia PigmentiPigmenti

XX--linked, lethal in linked, lethal in hemizygoushemizygous malesmalesVesicular rash in newborn periodVesicular rash in newborn periodNeonatal seizuresNeonatal seizuresPolymorphic pigmented lesions Polymorphic pigmented lesions develop in infancydevelop in infancy

IncontinentiaIncontinentia PigmentiPigmentiErythematousErythematous bullousbullous lesions at birthlesions at birthSecond stage crusting of lesions (Second stage crusting of lesions (verrucousverrucous))Third stage whorls, zebra stripes, speckles or Third stage whorls, zebra stripes, speckles or other patterns of pigmentationother patterns of pigmentationMicrocephaly and Microcephaly and micropolygyriamicropolygyriaMental retardationMental retardationDental anomalies and ocular abnormalitiesDental anomalies and ocular abnormalities

IncontinentiaIncontinentia PigmentiPigmenti

IncontinentiaIncontinentia PigmentiPigmenti

J Am Acad Dermatol 2002;47:169-87

IncontinentiaIncontinentia PigmentiPigmenti

Dental anomaliesDental anomalies——both primary and both primary and secondary dentitionsecondary dentition–– HypodontiaHypodontia (small teeth)(small teeth)–– Partial Partial anodontiaanodontia (lack of teeth)(lack of teeth)–– Delayed eruptionDelayed eruption–– Impacted dentitionImpacted dentition–– Malformed crowns (cone or pegMalformed crowns (cone or peg--shaped)shaped)

IncontinentiaIncontinentia PigmentiPigmenti

OphthalmicOphthalmic–– StrabismusStrabismus–– CataractsCataracts–– Optic atrophyOptic atrophy–– AnophthalmiaAnophthalmia (absence of eye)(absence of eye)–– MicrophthalmiaMicrophthalmia–– Retinal Retinal vasculopathyvasculopathy (Fig 1)(Fig 1)–– Changes such as Changes such as retrolentalretrolental fibroplasiafibroplasia

IncontinentiaIncontinentia PigmentiPigmenti

Central nervous system symptoms and findingsCentral nervous system symptoms and findings–– SeizuresSeizures–– Mental retardationMental retardation–– AtaxiaAtaxia–– Spastic abnormalitiesSpastic abnormalities–– Microcephaly Cerebral atrophy Microcephaly Cerebral atrophy –– HypoplasiaHypoplasia of corpus callosumof corpus callosum–– HydrocephalusHydrocephalus–– PorencephalicPorencephalic cystscysts–– Hemorrhagic necrosisHemorrhagic necrosis–– Neuronal heterotopiasNeuronal heterotopias

IncontinentiaIncontinentia PigmentiPigmenti

IncontinentiaIncontinentia PigmentiPigmenti

HypomelanosisHypomelanosis of Itoof ItoHypopigmentationHypopigmentation in whorlsin whorlsSeizuresSeizuresMental retardationMental retardationOphthalmologic anomaliesOphthalmologic anomaliesHeterotopiasHeterotopias

HypomelanosisHypomelanosis of Itoof Ito

Small 0.5Small 0.5--11--cm cm hypopigmentedhypopigmented or white or white maculesmacules coalesce to form coalesce to form reticulated patches along the lines of reticulated patches along the lines of BlaschkoBlaschko..–– The The maculesmacules cover more than 2 dermatomes and are often on both sides cover more than 2 dermatomes and are often on both sides

of the body.of the body.–– The patches are not symmetric.The patches are not symmetric.–– A Wood lamp enhances the pattern, especially in white patients.A Wood lamp enhances the pattern, especially in white patients.

DysmorphismDysmorphism::–– Cleft palateCleft palate–– HemihypertrophyHemihypertrophy–– Limb, hand, and/or foot abnormalitiesLimb, hand, and/or foot abnormalities–– Nail abnormalitiesNail abnormalities–– HypotoniaHypotonia–– Teeth abnormalitiesTeeth abnormalities–– Hair anomaliesHair anomalies–– Face and/or skull anomaliesFace and/or skull anomalies

HypomelanosisHypomelanosis of Itoof Ito

Familial Cancer DisordersFamilial Cancer Disorders--Disorders of GatekeepersDisorders of Gatekeepers

Von Von HippleHipple--LindauLindau SyndromeSyndromeNeurofibromatosis type 1Neurofibromatosis type 1NeurofibormatosisNeurofibormatosis type 2type 2Tuberous sclerosisTuberous sclerosis

NEUROFIBROMATOSIS TYPE 1NEUROFIBROMATOSIS TYPE 1

NF1 Molecular BiologyNF1 Molecular Biology

NF1 gene localized on chromosome 17q11.2 NF1 gene localized on chromosome 17q11.2 ~300 kb, contains 53 exons~300 kb, contains 53 exons–– intron 72b contains 3 previously identified genesintron 72b contains 3 previously identified genes–– intron 37 contains the adenylate kinase 3 pseudogeneintron 37 contains the adenylate kinase 3 pseudogene

Protein product is Protein product is neurofibrominneurofibromin–– 2818 amino acids2818 amino acids–– ? GTPase activator that regulates a tumor suppressor ? GTPase activator that regulates a tumor suppressor

genegene

NF1 GeneticsNF1 Genetics

Autosomal dominantAutosomal dominant–– Complete penetranceComplete penetrance

Half of the NF1 cases are new mutationsHalf of the NF1 cases are new mutationsMore than 200 different gene mutationsMore than 200 different gene mutations–– Most gene abnormality have been uniqueMost gene abnormality have been unique

Extremely variable expressionExtremely variable expression

Neurofibromatosis Type 1Neurofibromatosis Type 1

NF1, von Recklinghausen DiseaseNF1, von Recklinghausen DiseasePrevalencePrevalence-- 1/30001/3000No racial or ethnic predilection No racial or ethnic predilection –– 1/7800 in the USSR 1/7800 in the USSR –– 1.04/1000 in Israel military recruits1.04/1000 in Israel military recruits

Criteria for the diagnosis of NF1 Criteria for the diagnosis of NF1 requires two or more of the requires two or more of the following:following:

•• Six or more cafe'Six or more cafe'--auau--lait macules (over 5 mm in lait macules (over 5 mm in prepubertal individuals and over 15 mm in prepubertal individuals and over 15 mm in postpubertal individuals)postpubertal individuals)

•• Two or more neurofibromas of any type or one Two or more neurofibromas of any type or one plexiform neurofibroma.plexiform neurofibroma.

•• Freckling in the axillary or inguinal regionFreckling in the axillary or inguinal region•• Optic gliomaOptic glioma•• Two or more Lisch nodules (iris hamartomas)Two or more Lisch nodules (iris hamartomas)•• A distinctive osseous lesion such as sphenoid A distinctive osseous lesion such as sphenoid

dysplasia or thinning of long bone cortex with or dysplasia or thinning of long bone cortex with or without pseudarthrosiswithout pseudarthrosis

•• A firstA first--degree relative with NFdegree relative with NF--1 by the above 1 by the above criteriacriteria

NF1NF1

cafcaféé--auau--laitlait spotsspots

Pigmentation overlyingplexiform neurofibroma

Neurofibromatosis Type 1Neurofibromatosis Type 1

Axillary Freckling

Plexiform Neurofibroma of Plexiform Neurofibroma of the Facial Nervethe Facial Nerve

Clinical Feature

Incidence CONGENITAL(0-2 yrs)

PRESCHOOL (2-4 yrs)

LATE CHILDHOOD & ADOLESCENCE

(6-16 yrs)

ADULTHOOD (16+yrs)

Café au lait spots

-------------------->

Plexiform Diffuse neurofibroma-

25%

-------------------->

Superficial or nodul ar

-------------------->------------------->

Tibial dysplasia-

3 % -------------------->------------------->

Skinfold freckling

-----------------> --------------->

Optic glioma 15 – 20 % --------->-------------------> Learning disabilities

30 – 65 % -------------------> --------------->

NF1NF1Time Line For Time Line For ComplicationsComplications

CONGENITAL(0-2 yrs)

PRESCHOOL (2-4 yrs)

LATE CHILDHOOD & ADOLESCENCE

(6-16 yrs)

ADULTHOOD(16+yrs)

Hypertension -----------------> ---------------------> ------------------> Headaches 10 – 20 % -----------------> ---------------------> ------------------> Dermal neurofibroma

---------------------> ------------------>

Scoliosis 12 – 20 % ---------------------> Malignant peripheral nerve sheath tumors

1 – 4 % ----------------------> ------------------>

NF1NF1Time Line For Time Line For ComplicationsComplications

Macrocephaly and Somatic Growth in NF1Macrocephaly and Somatic Growth in NF1

•• Absolute Absolute macrocephalymacrocephaly (head (head circumference circumference > > 98 %98 %ileile) reported in 43) reported in 43--45% of patients with NF45% of patients with NF--11•• Recent NF multicenter studyRecent NF multicenter study--

•• 24% have macrocephaly (OFC >/=2 standard deviations 24% have macrocephaly (OFC >/=2 standard deviations above the population mean). above the population mean).

•• 13% of patients have short stature (>/=2 13% of patients have short stature (>/=2 standard deviations below the population mean)standard deviations below the population mean)

•• Szudek,JSzudek,J. et. al Growth in North American white children with neurofibro. et. al Growth in North American white children with neurofibromatosis 1 (NF1) matosis 1 (NF1) J. Med. Genetics 37:933, 2000J. Med. Genetics 37:933, 2000

Optic gliomaNormal

NF1NF1Other MRI AbnormalitiesOther MRI Abnormalities

Areas of increased T2 signal intensityAreas of increased T2 signal intensity–– 43 43 -- 79 % of NF1 in pediatric age group79 % of NF1 in pediatric age group–– MostMost-- multiple, no mass effect.multiple, no mass effect.–– PathPath-- atypical glial infiltrate, atypical glial infiltrate,

microcalcificaiton, and areas of microcalcificaiton, and areas of dysmyelination and spongy changes in dysmyelination and spongy changes in WM around lesion. WM around lesion.

Areas of increased T1 signal intensityAreas of increased T1 signal intensityVentricular enlargementVentricular enlargement

Learning is often affected in NF1 children. Learning is often affected in NF1 children. Visuospatial function is most clearly Visuospatial function is most clearly affected.affected.The brains of NF1 children are larger and The brains of NF1 children are larger and the pattern of growth of NF1 children the pattern of growth of NF1 children may be different.may be different.–– The increased brain size in NF1 children is The increased brain size in NF1 children is

due to increased gray and white matter.due to increased gray and white matter.–– Visual spatial function is one of the most Visual spatial function is one of the most

consistent deficits and has correlated with consistent deficits and has correlated with right hemisphere gray matter volume.right hemisphere gray matter volume.

ConclusionsConclusions

The brains of NF1 children also have The brains of NF1 children also have lowerlower NAA/creatine, and NAA/Cho NAA/creatine, and NAA/Cho ratios in the thalamusratios in the thalamus..T2 hyperintensities may be a marker for T2 hyperintensities may be a marker for a more diffuse processa more diffuse process..–– They may be positively correlated They may be positively correlated

with cognitive deficitswith cognitive deficits..

Conclusions Contd.Conclusions Contd.

ADC in NF1 children is significantly different from ADC in NF1 children is significantly different from other children but fractional other children but fractional aniosotropyaniosotropy is only is only different in the hippocampus. different in the hippocampus.

The areas of the brain with greatest ADC differences The areas of the brain with greatest ADC differences are those where we find significantly greater brain are those where we find significantly greater brain volume, the parietalvolume, the parietal--occipital and frontal cortex. occipital and frontal cortex. These same areas are thought to be important for These same areas are thought to be important for attention and visual spatial function. attention and visual spatial function.

Conclusions Contd.Conclusions Contd.

Neurofibromatosis Type 2Neurofibromatosis Type 2Bilateral acoustic Bilateral acoustic neuromasneuromas-- diagnosticdiagnosticOther tumorsOther tumors-- meningiomameningioma, , ependymomasependymomas, , spinal cord spinal cord astrocytomasastrocytomas, dorsal nerve , dorsal nerve schwannomasschwannomasSkin Skin hyperpigmentationhyperpigmentation is variableis variablePosterior Posterior subcapsularsubcapsular cataracts and cataracts and LischLischnodulesnodules

Tuberous SclerosisTuberous Sclerosis

Tuberous SclerosisTuberous Sclerosis

IncidenceIncidence-- 1 in 6000 1 in 6000 -- 90009000Dominant inheritance but a high frequency Dominant inheritance but a high frequency of spontaneous mutationof spontaneous mutation–– 56% to 86% spontaneous mutation56% to 86% spontaneous mutation

Variable expression within familiesVariable expression within families

Tuberous SclerosisTuberous Sclerosis

Gene LocationGene Location ProteinProteinTSC1TSC1 chromosome 9 qchromosome 9 q hamartinhamartinTSC2TSC2 chromosome 16 pchromosome 16 p tuberintuberin

Tuberous Sclerosis Tuberous Sclerosis Revised Diagnostic CriteriaRevised Diagnostic Criteria

Definite TSCDefinite TSC–– Two major feature orTwo major feature or–– One major plus 2 minorOne major plus 2 minorProbable TSCProbable TSC–– One major and one minorOne major and one minorPossible TSCPossible TSC–– One majorOne major–– 2 or more minor2 or more minor

Tuberous SclerosisTuberous SclerosisPrimary FeaturesPrimary Features–– Facial angiofibromasFacial angiofibromas–– Multiple Multiple ungualungual fibromasfibromas–– Cortical tubersCortical tubers–– SubependymalSubependymal nodules or giant cell nodules or giant cell astrocytomaastrocytoma–– Retinal Retinal hamartomashamartomas–– 3 or more 3 or more hypomelanotichypomelanotic maculesmacules–– ShagreenShagreen patchpatch–– Renal angiomyolipomaRenal angiomyolipoma–– Cardiac Cardiac rhabdomyomarhabdomyoma–– Pulmonary Pulmonary lymphangiomatosislymphangiomatosis

Tuberous SclerosisTuberous SclerosisSecondary featuresSecondary features–– Affected first degree relativeAffected first degree relative–– Dental enamel pitsDental enamel pits–– Bone cystsBone cysts–– Forehead plaqueForehead plaque–– Renal cystsRenal cysts-- renal renal angiomyuolipomaangiomyuolipoma–– Renal cystsRenal cysts-- histologichistologic–– HamartomatousHamartomatous rectal polyps rectal polyps –– Gingival Gingival fibromasfibromas

Tuberous SclerosisTuberous SclerosisCutaneous ManifestationsCutaneous Manifestations

HypomelanoticHypomelanotic maculesmacules-- 90 %90 %ShagreenShagreen patchpatch-- 20 20 -- 30 %30 %UngualUngual fibromafibroma-- 15 to 20 %15 to 20 %Facial Facial angiomaangioma (adenoma (adenoma sebaceumsebaceum))-- 75 %75 %Forehead plaqueForehead plaque““ConfettiConfetti”” hypopigmentedhypopigmented skin lesionsskin lesionsGingival Gingival fibromasfibromasPoliosisPoliosis

Tuberous SclerosisTuberous SclerosisHypopigmentedHypopigmented MaculeMacule

Tuberous SclerosisTuberous SclerosisHypopigmentedHypopigmented MaculeMacule-- WoodWood’’s s LampLamp

Tuberous SclerosisTuberous SclerosisEarly Adenoma Early Adenoma SebaceumSebaceum

Tuberous SclerosisTuberous SclerosisLate Adenoma Late Adenoma SebaceumSebaceum

Tuberous SclerosisTuberous SclerosisUngualUngual FibromaFibroma

Tuberous SclerosisTuberous SclerosisShagreenShagreen PatchPatch

Tuberous SclerosisTuberous SclerosisShagreenShagreen PatchPatch

Tuberous Sclerosis Tuberous Sclerosis Other ManifestationsOther Manifestations

CardovascularCardovascular–– cardiac cardiac rhabdomyomatarhabdomyomata-- 30 to 50 %30 to 50 %–– cardiac arrhythmiacardiac arrhythmia–– cardiac cardiac thromboembolismthromboembolism

RenalRenal–– renal angiomyolipomasrenal angiomyolipomas–– renal cystsrenal cysts

PulmonaryPulmonary–– 1%, females > males1%, females > males–– pulmonary pulmonary lymphangiomyomatosislymphangiomyomatosis–– symptoms include symptoms include pneumothoraxpneumothorax, , dyspneadyspnea, cough, , cough, hemoptysishemoptysis, ,

and pulmonary failureand pulmonary failure..

Tuberous Sclerosis Tuberous Sclerosis Neurologic ManifestationsNeurologic Manifestations

SeizuresSeizures-- often infantile spasmsoften infantile spasmsMental retardation and autisticMental retardation and autistic--like like behaviorbehavior-- 60%60%Focal neurologic deficitsFocal neurologic deficitsBrain tumorsBrain tumors–– 66--14% of TSC patients14% of TSC patients–– giant cell astrocytomagiant cell astrocytoma

Tuberous Sclerosis Gene Tuberous Sclerosis Gene FunctionFunction

Tumor suppressor genesTumor suppressor genesHamartomasHamartomas of tuberous sclerosis patients of tuberous sclerosis patients show loss of heterozygosity show loss of heterozygosity Sequence homologies at the protein level Sequence homologies at the protein level reveal a region of similarity between reveal a region of similarity between tuberintuberinand the and the GTPaseGTPase activating protein GAP3 activating protein GAP3

TS and Adjacent GenesTS and Adjacent Genes

A contiguous deletion that affects both A contiguous deletion that affects both TSC2 and PKD1 genes results in early onset TSC2 and PKD1 genes results in early onset polycystic kidney diseasepolycystic kidney diseaseSome patients with contiguous deletions are Some patients with contiguous deletions are milder because of somatic milder because of somatic mosaicismmosaicism

SturgeSturge WeberWeber

SturgeSturge--Weber SyndromeWeber SyndromeUnilateral or bilateral facial Unilateral or bilateral facial angiomaangioma in the in the distribution of the first branch of the distribution of the first branch of the trigeminal nervetrigeminal nerveIpsilateral intracranial vascular Ipsilateral intracranial vascular anomalieanomalie of of the capillaries and the capillaries and venulesvenules of the of the leptomeningesleptomeningesGlaucomaGlaucoma

SturgeSturge--Weber Syndrome MRIWeber Syndrome MRI

SturgeSturge Weber Neurological Weber Neurological ComplicationsComplications

HemiparesisHemiparesisSeizuresSeizuresDevelopmental DelayDevelopmental DelayHeadachesHeadaches

WyburnWyburn Mason SyndromeMason Syndrome

An uncommon disorder characterized by a An uncommon disorder characterized by a vascular malformation of the midbrain vascular malformation of the midbrain associated with a unilateral retinal AVM, associated with a unilateral retinal AVM, facial nevi, and mental changesfacial nevi, and mental changes

WyburnWyburn Mason SyndromeMason Syndrome

ArteriovenousArteriovenous malformations of the retina malformations of the retina and central nervous systemand central nervous systemRareRareNo sex predilectionNo sex predilectionVariable neurological abnormalities Variable neurological abnormalities

WyburnWyburn--Mason SyndromeMason Syndrome

Retina showing dilated vasculature in a child with reduced vision, seizures and facial vascular lesions.

von von HippelHippel LindauLindau DiseaseDisease

Diagnostic CriteriaDiagnostic Criteria–– One or more One or more hemangioblastomashemangioblastomas either at the either at the

same or different sitessame or different sites–– Other visceral lesionsOther visceral lesions–– Familial tumors Familial tumors

Urinary Urinary metanephrinemetanephrine level, and VMA are level, and VMA are elevated. elevated.

KlippelKlippel--TrenuanwayTrenuanway--WeberWeberSyndromeSyndrome

An uncommon neurocutaneous disorder An uncommon neurocutaneous disorder characterized by extensive skin characterized by extensive skin hemangiomashemangiomas appearing in a appearing in a dermatomaldermatomalpattern, and associated with pattern, and associated with hemangiomashemangiomasof the spinal cord. of the spinal cord. The lesions are unilateral and are often The lesions are unilateral and are often associated with osseous or muscular associated with osseous or muscular hypertrophy of the involved area. This may hypertrophy of the involved area. This may be a spinal variant of be a spinal variant of SturgeSturge--Weber. Pattern Weber. Pattern of inheritance unknown.of inheritance unknown.

KlippelKlippel--TreTre´́naunaynaunaysyndromesyndrome

J Am Acad Dermatol 2004;51:391-8.

OslerOsler--Weber Weber --RenduRendu SyndromeSyndrome

An uncommon disorder characterized by An uncommon disorder characterized by angiomasangiomasof the skin, mucous membranes, and nervous of the skin, mucous membranes, and nervous system. system. Autosomal dominant disorder Autosomal dominant disorder Development of multiple small red or purple Development of multiple small red or purple angiomasangiomas. These enlarge and may be the source of . These enlarge and may be the source of recurrent recurrent epistaxisepistaxis or GI or GU hemorrhages. or GI or GU hemorrhages. Scattered Scattered angiomasangiomas may develop in the brain or may develop in the brain or spinal cord, producing hemorrhage or localized spinal cord, producing hemorrhage or localized cerebral spinal dysfunction.cerebral spinal dysfunction.

Linear Linear SebaciousSebacious NevusNevus

Linear Nevus Linear Nevus SebaceusSebaceusSyndromeSyndrome

Linear patches of yellow papulesLinear patches of yellow papulesMental retardationMental retardationSeizuresSeizuresHemiparesisHemiparesisOcular abnormalitiesOcular abnormalities-- microphthalmiamicrophthalmia, , anophthalmiaanophthalmia, , choristomaschoristomas, and , and colobomatacolobomataof lids, iris, choroids and optic nerve.of lids, iris, choroids and optic nerve.

Linear Nevus Linear Nevus SebaceusSebaceusSyndromeSyndrome

Brain AbnormalitiesBrain Abnormalities–– HemiatrophyHemiatrophy–– LipomasLipomas

Congenital NevusCongenital Nevus

Congenital nevi are Congenital nevi are melanocyticmelanocytic nevi present at nevi present at birth. birth. –– They are probably best recognized as the large bathing They are probably best recognized as the large bathing

suit nevi that may cover large portions of the body. suit nevi that may cover large portions of the body. Giant congenital neviGiant congenital nevi–– InfantInfant-- usually larger than 6 cm on the trunk, 9 cm on usually larger than 6 cm on the trunk, 9 cm on

the scalp.the scalp.–– AdultAdult-- greater than 20 cm in its largest diameter in an greater than 20 cm in its largest diameter in an

adult. adult. The management of these larger lesions is The management of these larger lesions is controversial. controversial.

Neurocutaneous Neurocutaneous melanosismelanosis and and encephalocraniocutaneousencephalocraniocutaneouslipomatosislipomatosis

J Am Acad Dermatol 2002;47:S196-200.

Neurocutaneous Neurocutaneous melanosismelanosis and and encephalocraniocutaneousencephalocraniocutaneous lipomatosislipomatosis

Funduscopic View- Right eye fundoscopic view demonstrating multiple large chorioretinallacunae.

NEUROCUTANEOUS MELANOSISNEUROCUTANEOUS MELANOSIS

SignsSigns–– HydrocephalusHydrocephalus

MacrocephalyMacrocephalyIncreasing head circumferenceIncreasing head circumferenceBulging Bulging fontanellefontanelleSeizuresSeizuresDevelopmental delayDevelopmental delay

SymptomsSymptoms–– HeadacheHeadache

VomitingVomitingFailure to thriveFailure to thriveWeaknessWeaknessGait abnormalitiesGait abnormalitiesBladder or bowel dysfunctionBladder or bowel dysfunction

Neurocutaneous Neurocutaneous MelanosisMelanosis

–– DiagnosisDiagnosispresence of neurologic symptomspresence of neurologic symptomsincreased number of increased number of melanocytesmelanocytes within the central within the central nervous system associated with large cutaneous nevi nervous system associated with large cutaneous nevi or multiple smaller nevi. or multiple smaller nevi.

–– CNS CNS melanocytesmelanocytes are usually found in the are usually found in the anterior temporal lobes, cerebellum, thalami, anterior temporal lobes, cerebellum, thalami, and base of the frontal lobe and base of the frontal lobe

LargeLarge CongenitalCongenital MelanocyticMelanocytic NevusNevusMalignancy RiskMalignancy Risk

Lifetime risk for melanoma estimated between 4.5Lifetime risk for melanoma estimated between 4.5--10%10%

5 year cumulative risk of 2.3% and relative risk of 101 5 year cumulative risk of 2.3% and relative risk of 101 If melanoma develops, >50% develop <5 years and 70% If melanoma develops, >50% develop <5 years and 70% by age 10by age 10

Greater risk occurring on the axial site (head, neck, and/or Greater risk occurring on the axial site (head, neck, and/or trunk)trunk)

No reports of melanomas arising in nevi restricted to an No reports of melanomas arising in nevi restricted to an extremity or within congenital satellite neviextremity or within congenital satellite nevi

J Am Acad Dermatol 1997;36:409-416Arch Dermatol 1996;132:170-175Pediatrics 2000;106:736-741

ASSOCIATED FINDINGS WITH GIANT ASSOCIATED FINDINGS WITH GIANT CONGENITAL MELANOCYTIC NEVICONGENITAL MELANOCYTIC NEVI

LOCAL CHANGES LOCAL CHANGES

MALIGNANCIES MALIGNANCIES

MALFORMATIONSMALFORMATIONS

Loss of subcutaneous fatLoss of subcutaneous fatLimb Limb hypoplasiahypoplasiaRhabdomyosarcomaRhabdomyosarcomaLiposarcomaLiposarcomaNeuroblastomaNeuroblastomaPrimitive Primitive neuroectodermalneuroectodermaltumorstumorsMixed malignant Mixed malignant neoplasmsneoplasmsVascularVascularSupernumerary digitsSupernumerary digitsEar deformitiesEar deformitiesPreauricularPreauricular appendagesappendagesCryptorchidismCryptorchidismClub feetClub feet

Treatment of Giant Congenital Treatment of Giant Congenital MelanocyticMelanocyticNeviNevi

DermabasionDermabasion–– 12 patients treated between the first and fourteenth 12 patients treated between the first and fourteenth

week of life. week of life. 1010-- appreciable and stable reduction of the appreciable and stable reduction of the hyperpigmentationhyperpigmentation..66-- reconstruction using grafts and flaps was required.reconstruction using grafts and flaps was required.11-- developed minimal deviation melanomadeveloped minimal deviation melanoma

CurettageCurettage–– 16 patients treated during first 2 weeks of life16 patients treated during first 2 weeks of life

All had good cosmetic outcomeAll had good cosmetic outcomeNo melanoma No melanoma

Scand J Plast Reconstr Surg Hand Surg 2000 Dec;34(4):321-6

Arch Dermatol 2002 Jul;138(7):943-7

WaardenburgWaardenburg Syndrome Syndrome Type 1 & 2Type 1 & 2

Major criteriaMajor criteria–– Congenital Congenital sensorineuralsensorineural hearing loss hearing loss –– PigmentaryPigmentary disturbances of irisdisturbances of iris–– Complete Complete heterochromiaheterochromia iridumiridum, two eyes of different color , two eyes of different color –– Partial or segmental Partial or segmental heterochromiaheterochromia; segments of blue or brown ; segments of blue or brown

pigmentation in one or both eyes pigmentation in one or both eyes –– HypoplasticHypoplastic blue eyes, characteristic brilliant blue in both eyesblue eyes, characteristic brilliant blue in both eyes–– Hair Hair hypopigmentationhypopigmentation, white forelock , white forelock –– Dystopia Dystopia canthorumcanthorum, W > 1.95 averaged over affected family , W > 1.95 averaged over affected family

members (this was modified from the original proposal of W > members (this was modified from the original proposal of W > 2.07 in the light of experience) 2.07 in the light of experience)

–– Affected first degree relativeAffected first degree relative

Minor criteriaMinor criteria–– Congenital Congenital leukodermaleukoderma, several areas of , several areas of

hypopigmentedhypopigmented skin skin –– SynophyrysSynophyrys or medial eyebrow flare or medial eyebrow flare –– Broad and high nasal root Broad and high nasal root –– HypoplasiaHypoplasia of of alaealae nasinasi–– Premature Premature greyinggreying of hair, scalp hair of hair, scalp hair

predominantly white before age 30predominantly white before age 30

WaardenburgWaardenburg Syndrome Type 1 Syndrome Type 1 & 2& 2

Please RememberPlease Remember

No matter how hard you try, you can't No matter how hard you try, you can't baptize cats.baptize cats.

Never lick a steak knife. Never lick a steak knife.

KlippelKlippel--TreTre´́naunaynaunay SyndromeSyndromeLymphatic InvolvementLymphatic Involvement

Definite:Definite:–– LymphangiomaLymphangioma circumscriptumcircumscriptum–– MacrocysticMacrocystic disease seen on MRIdisease seen on MRI–– Malformation of Malformation of lymphaticslymphatics on on lymphoscintigraphylymphoscintigraphy

Probable:Probable:–– PseudoverrucousPseudoverrucous lymphedemalymphedema changes or changes or lymphedemalymphedema–– Recurrent Recurrent cellulitiscellulitis–– Vascular Vascular ectasiasectasias (blebs)(blebs)–– VerrucousVerrucous changes over stainchanges over stain

Possible:Possible:–– One episode of One episode of cellulitiscellulitis–– NonNon--pitting edemapitting edema–– No LM:No LM:–– Lacking any of the features aboveLacking any of the features above

J Am Acad Dermatol 2004;51:391-8.

Fabry'sFabry's DiseaseDisease

Caused by a deficit in alphaCaused by a deficit in alpha--galactosidasegalactosidaseleading to an accumulation of leading to an accumulation of ceramideceramidetrihexosidetrihexoside in the endothelium and media of in the endothelium and media of blood vessels. Although the skin lesions are blood vessels. Although the skin lesions are diagnostic, the vascular involvement tends diagnostic, the vascular involvement tends to be more diffuse.to be more diffuse.An XAn X--linked recessive disorder found mostly linked recessive disorder found mostly in males. Females tend to be in males. Females tend to be aysmptomaticaysmptomaticheterozygotesheterozygotes who can be diagnosed by who can be diagnosed by assaying alphaassaying alpha--galactosidasegalactosidase activityactivity

Fabry'sFabry's DiseaseDisease

Neurologic involvement consists of a Neurologic involvement consists of a painful painful polyneuropathypolyneuropathy caused by caused by ceramideceramide trihexosidetrihexoside deposition both deposition both perineurallyperineurally and and intraneurallyintraneurally. . Cerebral Cerebral thromboembolicthromboembolic lesions may lesions may be seen early in teens.be seen early in teens.

Fabry'sFabry's DiseaseDisease

AngiokeratomaAngiokeratoma corporiscorporis diffusumdiffusum a a genetic disorder of the nervous genetic disorder of the nervous system, and skin.system, and skin.Multiple small, flat, or slightly raised Multiple small, flat, or slightly raised telangiectasestelangiectases on the abdomen and on the abdomen and lower extremities ,lower extremities ,